Does hypometabolism constrain innate immune defense?

Many animals routinely make energetic trade-offs to adjust to environmental demands and these trade-offs often have significant implications for survival. For example, environmental hypoxia is commonly experienced by many organisms and is an energetically challenging condition because reduced oxygen availability constrains aerobic energy production, which can be lethal. Many hypoxia-tolerant species downregulate metabolic demands when oxygen is limited; however, certain physiological functions are obligatory and must be maintained despite the need to conserve energy in hypoxia.

Status of the Janus Kinase-Signal Transducer and Activator of Transcription (JAK-STAT) pathway in liver and skin of the freeze tolerant wood frog.

The wood frog (Rana sylvatica) has adapted full-body freezing and thawing as a means of sub-zero winter survival and early-breeding in ephemeral pools. One such protective process implicated recently in freeze-thaw tolerance is that of anti-apoptotic signaling, which has been proposed to play a cytoprotective role by modulating stress-induced death signals. This study employed the use of immunoblotting to examine response of a potent cell cycle and apoptosis regulator, known as the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway, to freezing and thawing in the liver and skin of the wood frog.

Markers of tissue remodeling and inflammation in the white and brown adipose tissues of a model hibernator.

The thirteen-lined ground squirrel is a model fat-storing hibernator that nearly doubles its weight in the fall to fuel metabolism with triglycerides throughout the winter months. Hibernator brown and white adipose tissue (BAT, WAT) are important to study in terms of their inflammatory profile and tissue remodeling mechanisms since controlled and natural regulation of these processes could inform new pharmacological interventions that limit oxidative stress and inflammation in the adipose tissues of humans suffering from obesity, promote non-shivering thermogenesis-mediated weight loss, or prevent tissue damage in transplantable organs emerging from cold-storage. Thus, markers of inflammation like cytokines and soluble receptors and tissue remodeling proteins such as matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) were investigated in normothermic, torpid, and arousing ground squirrels.

Isoflurane and low-level carbon monoxide exposures increase expression of pro-survival miRNA in neonatal mouse heart.

Anesthetics such as isoflurane are known to cause apoptosis in the developing mammalian brain. However, isoflurane may have protective effects on the heart via relieving ischemia and downregulating genes related to apoptosis. Ischemic preconditioning, e.

The Torpid State: Recent Advances in Metabolic Adaptations and Protective Mechanisms.

Torpor and hibernation are powerful strategies enabling animals to survive periods of low resource availability. The state of torpor results from an active and drastic reduction of an individual's metabolic rate (MR) associated with a relatively pronounced decrease in body temperature. To date, several forms of torpor have been described in all three mammalian subclasses, i.

MicroRNA expression patterns in the brown fat of hibernating 13-lined ground squirrels.

The sequence diversity of microRNAs (miRNAs) allows these potent regulators of mRNA fate to bind multiple transcripts, giving them the power to inhibit diverse cellular processes. Therefore, miRNAs may regulate metabolic rate suppression (also termed torpor), an adaptation used by capable species to reduce energy expenditure, minimize tissue damage, and prolong life. Small RNA-sequencing of brown fat from control (37 °C) and torpid (5-8 °C) ground squirrels revealed a central role for miRNAs in torpor.

Regulation of Peroxisome Proliferator-Activated Receptor Pathway During Torpor in the Garden Dormouse, .

Differential levels of n-6 and n-3 essential polyunsaturated fatty acids (PUFAs) are incorporated into the hibernator's diet in the fall season preceding prolonged, multi-days bouts of torpor, known as hibernation. Peroxisome proliferator-activated receptor (PPAR) transcriptional activators bind lipids and regulate genes involved in fatty acid transport, beta-oxidation, ketogenesis, and insulin sensitivity; essential processes for survival during torpor. Thus, the DNA-binding activity of PPARα, PPARδ, PPARγ, as well as the levels of PPARγ coactivator 1α (PGC-1α) and L-fatty acid binding protein (L-FABP) were investigated in the hibernating garden dormouse ().

Inflammasome signaling could be used to sense and respond to endogenous damage in brown but not white adipose tissue of a hibernating ground squirrel.

Small mammalian hibernators use metabolic suppression to enhance survival during the winter. Torpor is punctuated by periods of euthermia used to clear metabolic by-products and damaged cell components. The current study was performed to determine if the innate immune system, specifically NLRP and AIM2 inflammasome signaling, may detect and respond to cell stress during hibernation.

The Ratio of Linoleic and Linolenic Acid in the Pre-hibernation Diet Influences NFκB Signaling in Garden Dormice During Torpor.

The fatty acid composition of a pre-hibernation diet can influence the depth and duration of metabolic suppression achieved by hibernators. More specifically, a diet high in -6 polyunsaturated fatty acids (PUFAs) relative to -3 PUFAs is essential to maximize torpor expression. However, few studies have investigated how diets with different -6/-3 PUFA ratios change stress-inducible cell signaling.

Cold-inducible RNA-binding protein Cirp, but not Rbm3, may regulate transcript processing and protection in tissues of the hibernating ground squirrel.

RNA-binding proteins (RBPs) have important roles in transcription, pre-mRNA processing/transport, mRNA degradation, translation, and non-coding RNA processing, among others. RBPs that are expressed in response to cold stress, such as Cirp and Rbm3, could regulate RNA stability and translation in hibernating mammals that reduce their body temperatures from 37 °C to as low as 0-5 °C during torpor bouts. RBPs including Cirp, Rbm3, and stress-inducible HuR translocate from the nucleus to stabilize mRNAs in the cytoplasm, and thereby could regulate which mRNA transcripts are protected from degradation and are translated, versus stored, for future protein synthesis or degraded by nucleases during cell stress associated with metabolic rate depression.

The brains of six African mole-rat species show divergent responses to hypoxia.

Mole-rats are champions of self-preservation, with increased longevity compared with other rodents their size, strong antioxidant capabilities and specialized defenses against endogenous oxidative stress. However, how the brains of these subterranean mammals handle acute hypoxia is poorly understood. This study is the first to examine the molecular response to low oxygen in six different species of hypoxia-tolerant mole-rats from sub-Saharan Africa.

Angiogenic signaling in the lungs of a metabolically suppressed hibernating mammal ().

To conserve energy in times of limited resource availability, particularly during cold winters, hibernators suppress even the most basic of physiologic processes. Breathing rates decrease from 40 breaths/minute to less than 1 breath/min as they decrease body temperature from 37 °C to ambient. Nevertheless, after months of hibernation, these incredible mammals emerge from torpor unscathed.

The squirrel with the lagging eIF2: Global suppression of protein synthesis during torpor.

Hibernating mammals use strong metabolic rate depression and a reduction in body temperature to near-ambient to survive the cold winter months. During torpor, protein synthesis is suppressed but can resume during interbout arousals. The current study aimed to identify molecular targets responsible for the global suppression of protein synthesis during torpor as well as possible mechanisms that could allow for selective protein translation to continue over this time.

Temperature and serine phosphorylation regulate glycerol-3-phosphate dehydrogenase in skeletal muscle of hibernating Richardson's ground squirrels.

Glycerol-3-phosphate dehydrogenase (G3PDH) bridges carbohydrate and lipid metabolism by interconverting glycerol-3-phosphate (G3P) and dihydroxyacetone phosphate (DHAP). This reversible reaction converts G3P derived from triglyceride hydrolysis to DHAP that can then enter glycolysis or gluconeogenesis and, in the reverse reaction, makes G3P for use in triglyceride biosynthesis. Small hibernating mammals rely almost exclusively on triglyceride reserves as their fuel for energy production during torpor and the recovery of glycerol after lipolysis is an important source of carbohydrate over the nonfeeding winter months.

Pro-inflammatory AGE-RAGE signaling is activated during arousal from hibernation in ground squirrel adipose.

Background: Inflammation is generally suppressed during hibernation, but select tissues (e.g. lung) have been shown to activate both antioxidant and pro-inflammatory pathways, particularly during arousal from torpor when breathing rates increase and oxidative metabolism fueling the rewarming process produces more reactive oxygen species.

Potential role for microRNA in regulating hypoxia-induced metabolic suppression in jumbo squids.

At night, Humboldt squid (Dosidicus gigas) rise to the ocean's surface to feed, but come morning, they descend into the ocean's oxygen minimum zone where they can avoid predators but must deal with severe hypoxia, high pressure, and very cold water. To survive this extreme environment, squid use various adaptations to enter a hypometabolic state characterized by metabolic rate suppression by 35-52%, relative to normoxic conditions. The molecular mechanisms facilitating this metabolic flexibility have yet to be elucidated in hypometabolic squid.

Tissue-specific response of carbohydrate-responsive element binding protein (ChREBP) to mammalian hibernation in 13-lined ground squirrels.

Mammalian hibernation is characterized by a general suppression of energy expensive processes and a switch to lipid oxidation as the primary fuel source. Glucose-responsive carbohydrate responsive element binding protein (ChREBP) has yet to be studied in hibernating organisms, which prepare for the cold winter months by feeding until they exhibit an obesity-like state that is accompanied by naturally-induced and completely reversible insulin resistance. Studying ChREBP expression and activity in the hibernating 13-lined ground squirrel is important to better understand the molecular mechanisms that regulate energy metabolism under cellular stress.

Turn down genes for WAT? Activation of anti-apoptosis pathways protects white adipose tissue in metabolically depressed thirteen-lined ground squirrels.

During hibernation, the metabolic rate of thirteen-lined ground squirrels (Ictidomys tridecemlineatus) can drop to <5 % of normal resting rate at 37 °C, core body temperature can decrease to as low as 1-5 °C, and heart rate can fall from 350-400 to 5-10 bpm. Energy saved by hibernating allows squirrels to survive the winter when food is scarce, and living off lipid reserves in white adipose tissue (WAT) is crucial. While hibernating, some energy must be used to cope with conditions that would normally be damaging for mammals (e.

Response of the JAK-STAT pathway to mammalian hibernation in 13-lined ground squirrel striated muscle.

Over the course of the torpor-arousal cycle, hibernators must make behavioral, physiological, and molecular rearrangements in order to keep a very low metabolic rate and retain organ viability. 13-lined ground squirrels (Ictidomys tridecemlineatus) remain immobile during hibernation, and although the mechanisms of skeletal muscle survival are largely unknown, studies have shown minimal muscle loss in hibernating organisms. Additionally, the ground squirrel heart undergoes cold-stress, reversible cardiac hypertrophy, and ischemia-reperfusion without experiencing fatal impairment.